Mackensen A, Galanos C, Engelhardt R
Medizinische Klinik I der Albert-Ludwigs-Universität, Freiburg, Germany.
Blood. 1991 Dec 15;78(12):3254-8.
Intravenous (IV) administration of purified lipopolysaccharide (LPS) from Salmonella abortus equi to cancer patients induces the formation of high amounts of endogenous cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). On repeated administration of LPS at 2-week intervals, a marked downregulation of the cytokine response was observed, especially between the first and the second challenge. This study sought to determine whether it would be possible to prevent this downregulation by pretreating patients with interferon-gamma (IFN-gamma), which is known to enhance cytokine production by monocytes and macrophages in vitro. Ten patients with disseminated cancer received a first injection of 4.0 ng LPS/kg. Thereafter, patients were divided into two groups. One group received two further LPS injections (4.0 ng/kg) at 2-week intervals. The second group was pretreated (-12 hours) with 50 micrograms IFN-gamma subcutaneously (SC) before the second and third LPS challenge. To prevent constitutional side effects such as fever and chills, patients received 1,600 mg ibuprofen orally before LPS injection. The results of the current study demonstrate that apart from TNF-alpha and IL-6, two other cytokines, interleukin-8 (IL-8) and granulocyte colony-stimulating factor (G-CSF) are produced in cancer patients in response to LPS. LPS application at 2-week intervals resulted in a transient attenuation of all cytokines (TNF-alpha, IL-6, IL-8, G-CSF) on the second challenge. In the case of TNF-alpha, IL-6, and G-CSF, pretreatment with IFN-gamma not only prevented the downregulation, but enhanced the production of these cytokines to levels higher than those obtained after the first LPS challenge. In contrast, the downregulation of IL-8 remained unaffected by IFN-gamma pretreatment. Further studies are warranted to determine whether the prevention of cytokine downregulation by IFN-gamma following repeated LPS injections is of clinical relevance in respect to the antitumor activity of LPS.
给癌症患者静脉注射（IV）来自马流产沙门氏菌的纯化脂多糖（LPS）会诱导大量内源性细胞因子的形成，如肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）。以2周的间隔重复注射LPS时，观察到细胞因子反应明显下调，尤其是在第一次和第二次刺激之间。本研究旨在确定是否可以通过用干扰素-γ（IFN-γ）预处理患者来预防这种下调，已知IFN-γ在体外可增强单核细胞和巨噬细胞的细胞因子产生。10例播散性癌症患者接受了首次4.0 ng LPS/kg的注射。此后，患者被分为两组。一组每隔2周再接受两次LPS注射（4.0 ng/kg）。第二组在第二次和第三次LPS刺激前皮下注射（SC）50微克IFN-γ进行预处理（-12小时）。为防止发热和寒战等全身副作用，患者在LPS注射前口服1600毫克布洛芬。当前研究结果表明，除了TNF-α和IL-6外，癌症患者对LPS还会产生另外两种细胞因子，即白细胞介素-8（IL-8）和粒细胞集落刺激因子（G-CSF）。每隔2周应用LPS导致第二次刺激时所有细胞因子（TNF-α、IL-6、IL-8、G-CSF）短暂减弱。对于TNF-α、IL-6和G-CSF，用IFN-γ预处理不仅防止了下调，还将这些细胞因子的产生提高到高于第一次LPS刺激后获得的水平。相比之下，IL-8的下调不受IFN-γ预处理的影响。有必要进行进一步研究，以确定重复注射LPS后IFN-γ预防细胞因子下调在LPS的抗肿瘤活性方面是否具有临床相关性。
